rs3807153

Positions:

• chr7-138733046-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020632.3(ATP6V0A4):​c.1739T>C​(p.Met580Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,613,950 control chromosomes in the GnomAD database, including 3,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M580I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.091 (1002 hom., cov: 31)
  • Exomes 𝑓: 0.056 (2997 hom.)
• Consequence: ATP6V0A4 NM_020632.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:6
• Conservation: PhyloP100: 9.32

Genes affected

ATP6V0A4 (HGNC:866): (ATPase H+ transporting V0 subunit a4) This gene encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular compartments of eukaryotic cells. V-ATPase dependent acidification is necessary for such intracellular processes as protein sorting, zymogen activation, receptor-mediated endocytosis, and synaptic vesicle proton gradient generation. V-ATPase is composed of a cytosolic V1 domain and a transmembrane V0 domain. The V1 domain consists of three A and three B subunits, two G subunits plus the C, D, E, F, and H subunits. The V1 domain contains the ATP catalytic site. The V0 domain consists of five different subunits: a, c, c', c'', and d. This gene is one of four genes in man and mouse that encode different isoforms of the a subunit. Alternatively spliced transcript variants encoding the same protein have been described. Mutations in this gene are associated with renal tubular acidosis associated with preserved hearing. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022696257).
• BP6: Variant 7-138733046-A-G is Benign according to our data. Variant chr7-138733046-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 5154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-138733046-A-G is described in Lovd as [Benign]. Variant chr7-138733046-A-G is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.191 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6V0A4	NM_020632.3	c.1739T>C	p.Met580Thr	missense_variant	17/22	ENST00000310018.7
ATP6V0A4	NM_130840.3	c.1739T>C	p.Met580Thr	missense_variant	16/21
ATP6V0A4	NM_130841.3	c.1739T>C	p.Met580Thr	missense_variant	16/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP6V0A4	ENST00000310018.7	c.1739T>C	p.Met580Thr	missense_variant	17/22	1	NM_020632.3	P1

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 13799 AN: 152026 Hom.: 992 Cov.: 31

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.0985

Gnomad EAS AF: 0.0560

Gnomad SAS AF: 0.119

Gnomad FIN AF: 0.0365

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0900

GnomAD3 exomes AF: 0.0658 AC: 16551 AN: 251412 Hom.: 819 AF XY: 0.0666 AC XY: 9043 AN XY: 135866

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.0376

Gnomad ASJ exome AF: 0.0939

Gnomad EAS exome AF: 0.0546

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0458

Gnomad OTH exome AF: 0.0601

GnomAD4 exome AF: 0.0559 AC: 81714 AN: 1461806 Hom.: 2997 Cov.: 41 AF XY: 0.0571 AC XY: 41515 AN XY: 727222

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0397

Gnomad4 ASJ exome AF: 0.0926

Gnomad4 EAS exome AF: 0.0679

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0464

Gnomad4 OTH exome AF: 0.0672

GnomAD4 genome AF: 0.0910 AC: 13851 AN: 152144 Hom.: 1002 Cov.: 31 AF XY: 0.0908 AC XY: 6756 AN XY: 74382

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.0554

Gnomad4 ASJ AF: 0.0985

Gnomad4 EAS AF: 0.0559

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0365

Gnomad4 NFE AF: 0.0455

Gnomad4 OTH AF: 0.0942

Alfa AF: 0.0577 Hom.: 882

Bravo AF: 0.0959

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0496 AC: 191

ESP6500AA AF: 0.185 AC: 817

ESP6500EA AF: 0.0479 AC: 412

ExAC AF: 0.0691 AC: 8390

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.0478

EpiControl AF: 0.0468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 16611712, 27884173, 10973252, 20981092, 24252324) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Autosomal recessive distal renal tubular acidosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 25, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D;D;D;.;.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0023	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;M;M;.;.;M
MutationTaster	Benign	0.0000017	P;P;P
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.8	D;D;.;.;.;D
REVEL	Pathogenic	0.65
Sift	Benign	0.032	D;D;.;.;.;D
Sift4G	Uncertain	0.040	D;D;.;.;.;D
Polyphen		0.77	P;P;P;.;.;P
Vest4		0.26
MPC		0.41
ClinPred		0.051	T
GERP RS		5.8
Varity_R		0.42
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3807153; hg19: chr7-138417791; COSMIC: COSV59474048; COSMIC: COSV59474048;